Established murine lupus nephritis does not respond to exogenous interleukin-1 receptor antagonist; a role for the endogenous molecule?

Interleukin 1β (IL-1β) is a potent inflammatory cytokine and IL-1β gene expression is elevated in the kidneys of mice with lupus nephritis. This study was designed to examine whether pharmacological administration of the IL-1 receptor antagonist (IL-lra) would reduce the inflammation in MRL lpr/lpr mice with lupus nephritis. Human recombinant IL-1ra (RA) or saline (SA) was infused by intraperitoneal osmotic minipumps in 16 week old mice (n = 9, group RA or n = 12, group SA, respectively). Age matched MRL + / + mice served as normal controls. At the end of 4 weeks of treatment glomerular filtration rates (5.4 ± 0.4 vs 5.6 ± 0.4 ml/min/kg BW), proteinuria (6.0 ± 1.0 vs 5.5 ± 1.2 μg IgG/day) glomerular volumes (571 ± 30 vs 509 ± 25 μm³ × 10³), mesangial volumes (172 ± 23 vs 158 ± 17 μm³ × 10³), and cells/glomerulus (519 ± 51 vs 506 ± 47) were not significantly different between RA and SA groups respectively. There was also no significant differences in spleen sizes, plasma IgG and anti-dsDNA antibody levels despite achieving levels of IL-lra of over 0.8 μg/ml in RA mice. Circulating IL-1 was not detected by bioassay in the plasma of diseased or normal mice. In fact, diseased, saline treated mouse plasma inhibited the cell proliferation assay in the presence of IL-1, and dilution studies showed that the endogenous inhibitors were of high titre. Although IL-1 may play a role in the renal injury of lupus nephritis, pharmacological inhibition with IL-lra in animals with established injury is without effect. Evidence would suggest that endogenous inhibitors already provide sufficient protection against IL-1 mediated inflammation.